VOLULITE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VOLUME (VOLULYTE)

Composition:

Active substances: 1000 ml of infusion solution contains:

poly(0-2-hydroxyethyl) starch 130/0.4 60.0 g

sodium acetate trihydrate 4.63 g

sodium chloride 6.02 g

potassium chloride 0.30 g

magnesium chloride hexahydrate 0.30 g;

Excipients: sodium hydroxide and hydrochloric acid diluted (for pH adjustment), water for injections.

Electrolytes:

Na+ 137.0 mmol/l,

K+ 4.0 mmol/l,

Mg++ 1.5 mmol/l,

Cl- 110.0 mmol/l,

CH3COO- 34.0 mmol/l.

Theoretical osmolarity: 286.5 mOsmol/l,

Titratable acidity: < 2.5 mmol NaOH/l;

pH: 5.7 – 6.5.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear or slightly opalescent, colorless or slightly yellow solution.

Pharmacotherapeutic group. Plasma substitutes and plasma protein fractions.

ATC code B05A A07.

Pharmacological Properties.

Pharmacodynamics. The active ingredient of Volulyte is hydroxyethyl starch 130/0.4 – a starch derivative produced from waxy maize starch (molar substitution 0.38–0.45 g), consisting of a glucose polymer (amylopectin). Volulyte is a synthetic colloid for volume replacement. Its pharmacological properties depend on the degree of molar substitution with hydroxyethyl groups (0.4), average molecular weight (130,000 Da), concentration (6%), substitution ratio (C2/C6 ratio) of approximately 8:12, as well as dosage and infusion rate. To describe the molecular weight and molar substitution characteristics of hydroxyethyl starch in Volulyte, the compound is designated as hydroxyethyl starch 130/0.4. The low molar substitution, medium molecular weight, and narrow molecular weight distribution of HES 130/0.4 contained in Volulyte contribute to its favorable effects on pharmacokinetics and intravascular volume.

Infusion of 500 ml of Volulyte administered over 30 minutes to volunteers resulted in a plateau-like increase in volume of approximately 100% of the infused volume, which is maintained for approximately 4 to 6 hours.

Isovolemic exchange transfusion with Volulyte maintains blood volume for at least 6 hours.

Volulyte contains the electrolytes sodium (Na+), potassium (K+), magnesium (Mg++), chloride (Cl-), and acetate (CH3COO-) in an isotonic solution. Acetate is a metabolizable anion that is oxidized in various organs and has an alkalizing effect.

Volulyte contains a low amount of chloride and therefore counteracts the development of hyperchloremic metabolic acidosis, especially when large infusion volumes are required or in cases at risk of developing metabolic acidosis.

In cardiac surgery, chloride levels were significantly lower and base excess less negative when Volulyte was used compared to HES 130/0.4 (6%) in 0.9% sodium chloride solution.

Treatment of pregnant women undergoing cesarean section

Limited clinical data are available on the use of a single dose of HES 130/0.4 (6%) in 0.9% sodium chloride solution in pregnant women during cesarean section under spinal anesthesia. The incidence of hypotension was significantly lower with HES 130/0.4 (6%) compared to control with crystalloid solution (36.6% vs. 55.3%).

Overall efficacy assessment showed significant advantages of HES 130/0.4 (6%) over crystalloid solutions in preventing hypotension and in cases of severe hypotension.

Pharmacokinetics. The pharmacokinetics of HES are complex and depend on the molecular weight and degree of molecular substitution of the substance. After intravenous administration, HES molecules smaller than 60,000–70,000 Da (the renal filtration threshold) are rapidly excreted in urine, while larger molecules, including those of Volulyte, are degraded by plasma α-amylase and subsequently excreted by the kidneys.

The average molecular weight of Volulyte in plasma in vivo in the first minutes after infusion is 70,000–80,000 Da and exceeds the renal filtration threshold throughout the treatment period.

The volume of distribution is approximately 5.9 L. Thirty minutes after the end of Volulyte infusion, its plasma concentration is 75% of the maximum, decreasing to 14% after 6 hours.

After a single dose of 500 ml of Volulyte, HES molecules are almost completely eliminated from the body within 24 hours.

Following administration of 500 ml of Volulyte, its plasma clearance is 31.4 ml/min. After a single 500 ml dose, the plasma half-life in the first phase is 1.4 hours and in the second phase is 12.1 hours.

In patients with stable renal impairment (mild to severe) and creatinine clearance (CrCl) < 50 ml/min, the area under the pharmacokinetic curve (AUC) was moderately higher (1.7-fold) than in patients with CrCl > 50 ml/min at the same dose (500 ml). Renal impairment did not affect the terminal elimination half-life or the maximum plasma concentration of HES. With CrCl > 30 ml/min, 59% of the administered dose was excreted in urine; with CrCl of 15–30 ml/min, 51% was excreted.

Daily infusion of 500 ml of a 10% solution containing HES 130/0.4 for 10 days in volunteers did not result in significant accumulation of the drug in plasma.

In an additional pharmacokinetic study, eight stable patients with end-stage renal disease (ESRD) undergoing hemodialysis received a single dose of 250 ml (15 g) of HES 130/0.4 (6%). During a 2-hour hemodialysis session (500 ml dialysate per minute, HD Highflux FX 50 filter, Fresenius Medical Care, Germany), 3.6 g (24% of the dose) of HES was removed. After 24 hours, the mean plasma concentration of HES was 0.7 mg/ml. After 96 hours, the mean plasma concentration of HES in plasma was 0.25 mg/ml.

HES 130/0.4 (6%) is contraindicated in patients undergoing hemodialysis.

Clinical characteristics.

Indications.

Hypovolemia caused by acute blood loss in cases where the use of crystalloids alone is considered insufficient.

Contraindications.

• Hypersensitivity to the components of the drug;
• sepsis;
• burns;
• renal failure or renal replacement therapy;
• intracranial or cerebral hemorrhage;
• critical condition of the patient (usually patients in intensive care units);
• hyperhydration;
• pulmonary edema;
• dehydration;
• severe hyperkalemia;
• severe hypernatremia or severe hyperchloremia;
• severe hepatic dysfunction;
• existing coagulation or blood clotting disorders;
• presence of transplanted organs in the patient;
• clinical conditions where volume overload is a potential problem, especially in cases of pulmonary edema and congestive heart failure.

Interaction with other medicinal products and other types of interactions.

To date, cases of interaction of Volulyte with other medicinal products are unknown.

When co-administering other medicinal products, it should be taken into account that they may cause potassium or sodium retention.

During administration of HES, serum amylase levels may temporarily increase, which may interfere with the diagnosis of pancreatitis.

At high doses, dilution effects may lead to decreased levels of blood clotting factors and other plasma proteins, as well as reduced hematocrit.

Special precautions for use.

The occurrence of anaphylactic/anaphylactoid reactions such as hypersensitivity, mild flu-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiac pulmonary edema has been associated with hydroxyethyl starch-containing solutions.

Due to the risk of allergic (anaphylactic/anaphylactoid) reactions, the patient's condition must be closely monitored and the infusion administered at a low rate. If a hypersensitivity reaction occurs, administration of the drug should be stopped immediately and appropriate therapeutic and supportive measures should be initiated until symptoms resolve.

Currently, there are no reliable data on the long-term safety of HES use in post-surgical and trauma patients. Before prescribing HES to such patients, the expected benefit should be carefully weighed against the uncertainty regarding long-term safety, and alternative treatment options should be considered.

HES is contraindicated in patients with renal insufficiency and in patients undergoing renal replacement therapy. Administration of HES should be discontinued at the first signs of kidney injury.

Cases requiring renal replacement therapy have been reported within 90 days following HES infusion. Renal function should be monitored in patients for at least 90 days.

Particular caution should be exercised when treating patients with impaired liver function. Also, pronounced hemodilution resulting from high-dose HES infusions should be avoided in the treatment of hypovolemic patients.

Volulyte is not a substitute for red blood cells or plasma coagulation factors.

Administration of HES should be discontinued at the first signs of coagulopathy. If repeated administration is necessary, coagulation parameters should be closely monitored.

The use of HES is not recommended in patients undergoing open-heart surgery combined with cardiopulmonary bypass due to the risk of excessive bleeding.

Volume overload due to overdose or too rapid infusion should be avoided, especially in patients with cardiovascular or pulmonary disease. Electrolyte levels, fluid balance, renal function, and acid-base balance should be closely monitored.

In cases of severe dehydration, crystalloid solutions should be administered. Adequate fluid should generally be given to prevent dehydration. Particular attention should be paid to patients with electrolyte imbalances.

In metabolic alkalosis and clinical situations where alkalinization should be avoided, solutions based on sodium chloride solution (a similar product containing HES 130/0.4 in 0.9% sodium chloride solution) should be preferred over alkalinizing agents such as Volulyte.

Use during pregnancy or breastfeeding.

There are no clinical data on the use of Volulyte during pregnancy. Limited clinical study data exist on the use of HES 130/0.4 (6%) in pregnant women undergoing cesarean section under spinal anesthesia. The incidence of hypotension was significantly lower (36.6%) with HES (6%) compared to crystalloid solutions (55.3%). Overall assessment of the efficacy of HES for prevention of hypotension and avoidance of serious hypotensive complications shows significant advantages over crystalloid solutions. Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. No signs of teratogenicity were observed. No negative effects on pregnant women or newborns were found when HES was used with 0.9% sodium chloride solution. Volulyte may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

It is unknown whether the drug is excreted in breast milk. Since many drugs are excreted in breast milk, caution should be exercised when administering Volulyte.

The decision to continue or discontinue breastfeeding during Volulyte therapy should be made considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Ability to affect reaction speed when driving or operating machinery.

The drug does not affect the ability to drive or operate other machinery.

Method of Administration and Dosage

For intravenous infusion only. For single use only.

Use only a clear solution free from particulate matter, immediately after opening an undamaged package.

Do not use the medicinal product after the expiry date. Any unused solution should be discarded.

HES should be administered at the lowest effective dose for the shortest possible duration. Treatment must be accompanied by continuous hemodynamic monitoring and should be discontinued immediately once appropriate hemodynamic parameters are achieved.

The use of HES should be limited to the initial phase of circulatory volume resuscitation in hypovolemia, with a maximum interval of 24 hours.

The first 10–20 mL of the solution should be administered slowly. The patient must be under close observation (due to the possibility of anaphylactic/anaphylactoid reactions).

Daily dosage and infusion rate depend on the extent of blood loss, hemodynamic support or restoration, and the effect of hemodilution.

The maximum daily dose of Volulyte is 30 mL/kg.

Children.

Data on the use of HES in children are limited; therefore, these solutions are not recommended for use in pediatric patients.

Overdose.

As with other plasma substitutes, overdose of Volulyte may lead to circulatory overload (e.g., pulmonary edema). In such cases, infusion must be stopped immediately, and a diuretic should be administered if necessary.

Side effects

Side effects are classified by organ systems and by frequency of occurrence: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000, frequency not known (cannot be estimated from available data).

Blood and lymphatic system.

Rare (high volumes). Administration of hydroxyethyl starch (HES) may lead to coagulation disorders, which are dose-dependent.

Immune system.

Rare. Medicinal products containing HES may cause anaphylactic/anaphylactoid reactions (hypersensitivity, mild flu-like symptoms, bradycardia, tachycardia, bronchospasm, non-cardiogenic pulmonary edema). In such cases, administration of the product must be immediately discontinued and appropriate measures taken.

Skin and subcutaneous tissue.

Common (dose-dependent). Prolonged administration of high volumes of HES may cause skin pruritus, a well-known adverse effect of these products.

Pruritus may appear only several weeks after the last administration and may persist for several months.

Hepatobiliary disorders.

Frequency not known (cannot be estimated from available data): liver injury.

Renal and urinary disorders.

Frequency not known (cannot be estimated from available data): kidney injury.

Laboratory findings.

Common (dose-dependent). During administration of HES, serum amylase levels may increase, which may interfere with the diagnosis of pancreatitis.

Increased amylase activity is due to the formation of amylase-HES complexes, which are slowly eliminated; elevated amylase activity does not indicate the presence of pancreatitis.

At high doses, the dilution effect may lead to dilution of blood components, reduced hematocrit, and decreased coagulation factors and other plasma proteins.

Shelf life.

3 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 25 °C. Do not freeze.

Incompatibilities.

Mixing Volulyte with other medicinal products should be avoided. In exceptional cases where mixing with other drugs is necessary, compatibility (turbidity or precipitation) should be considered, mixing should be performed under aseptic conditions, and the solution should be thoroughly mixed.

Packaging.

250 or 500 ml in a freeflex bag.

250 or 500 ml in a freeflex bag; 20 or 00 freeflex bags in a cardboard outer box.

Prescription category.

Prescription only.

Manufacturer.

Fresenius Kabi Deutschland GmbH.

Manufacturer's address and place of business.

Freseniusstraße 1, 61169 Friedberg, Germany.

Marketing Authorization Holder.

Fresenius Kabi Deutschland GmbH.

Address of the Marketing Authorization Holder and/or its representative.

Else-Kröner-Straße 1, 61352 Bad Homburg, Germany.